Department of Drug Resistance Diagnostics

Mission

To
improve our knowledge in the development, survival and
spread of drug resistance in malaria parasites and to
monitor the extent of drug resistance and efficacy of
standard and new antimalaral drugs in areas of interest
to ADF. The department explores and evaluates novel
malaria detection/diagnosis methods including molecular
and various rapid diagnostic kits. The department is
engaged in studies investigating P. vivax
genetics that determine or correlate with relapses of
infections.

Current Research Projects

1. Mechanisms of resistance to standard and newly
developed antimalarial drugs:

Chloroquine resistance in P. vivax:
searching for molecular correlates for chloroquine
resistance in P. vivax and its correlation
with in vivo and in vitro susceptibility to chloroquine
(in collaboration with Menzies School of Health
Research)

Atovaquone resistance in P. falciparum:
established that genetic mutations resulted from
atovaquone selection are located in the drug binding
site in cytochrome b and correlate with resistance to
atovaquone. The implications of these mutations in
resistance to Malarone are under investigation.

Sulfa resistance in P. vivax: Using
molecular biology methods and molecular modelling, we
established that mechanism of innate resistance to
sulfa drugs in P. vivax is determined by a
single amino acid in the drug binding site in pvDHPS.
P. vivax can also acquire resistance to sulfa
drugs by changing several other amino acids at the drug
binding site. Further investigations are under way to
examine the effect of these mutations in P.
falciparum systems and to test a variety of sulfa
drugs on PvDHPS in this system.

Antifolate resistance in P. vivax.
Investigations of genetic mutations in P.vivax
DHFR and DHPS and their impact on the susceptibilities
to conventional and new antimalarial antifolate drugs
are underway using the state of art transfaction
technology.

Artemisinin resistance: Investigating the
development of parasites following exposures to
artemisinin derivatives and possible linkage with
treatment failures (in collaboration with University of
South Florida, USA).

2. Molecular evaluation of antimalarial drugs and drug
combinations trailing in various settings.

In collaboration with MERLIN, the department has
performed molecular analysis on parasite diversity and
allelic types for a chloroquine and Fansidar trial in
East Timor, providing information on malaria transmission
in the area and more accurate efficacy data by
distinguishing new infections from recrudescences.

3. Evolution of drug resistance

Monitor chloroquine resistance and investigate the
evolution of chloroquine resistance in Asia-Pacific
Region and other regions of interest (in collaboration
with WRAIR , JIPD and HPITD China).

Monitor the extent of sulfadoxine and pyrimethamine
(SP) resistance in P. vivax: investigate
mutations in P. vivax DHFR and DHPS in
parasites collected from Asia, South-East Asia and
Pacific regions and their association with in vitro
susceptibility to SP.

Role of antigenic variation in the development,
survival and spread of drug resistance (NIH funded
project): Investigating antigenic switch rates and
switch processes in P. falciparum, and the
influence of antigenic variation on the development,
survival and spread of drug resistance by using
molecular biology methods and mathematical modelling.

4. P.
vivax genetics and relapses

Despite the use of radical cure regimens, post
operational relapses of P. vivax infections in
ADF personnel have become a major health problem.
Studies in parasite genetics are under way to
investigate factors that associated with increased risk
of relapses.

5. Improve rapid malaria diagnostic tests.

Many rapid diagnostic tests (RDTs) for P.
falciparum have been developed and are
commercially available. Most of these RDTs are based on
detecting parasite antigens in patient's blood. The
detection sensitivity of these kits is highly variable.
In collaboration with WPRO/WHO and FIND we are
investigating the possible causes of the sensitivity
variation. Our research focus on defining genetic
diversity in parasite antigens, difference in the level
of antigens produced by parasites and the variation in
epitopes recognised by monoclonal antibodies. The study
outcome will help the selection and quality control of
RDTs, as well as help to improve the detection
sensitivity of malaria RDTs .

6. Molecular Diagnosis

For assisting microscopic confirmation of malaria
infections, we have established PCR-based detection for
4 human malaria species. We will continue to improve
out capacity to perform multiplex PCR and develop field
adaptable PCR methods. Currently, the department is
actively involved in the AusAID Pacific Malaria
Initiatives. We are investigating the prevalence of the
malaria infections and the transmission parameters in
Vanuatu and Solomon Islands using molecular tools.

Training

Postgraduates: Hons, Masters and PhD;

Short term training for scientists from developing
countries: Molecular- based techniques: PCR,
genotyping, and resistance mutation detections;